Abstract:
:The clinical advancement of HIV-1 attachment inhibitors was hindered initially by poor bioavailability. Attempts to identify improved candidates revealed that solubility and dissolution-rate-limited absorption are barriers to achieving adequate antiviral plasma levels. This was mitigated by forming nanosized drugs or by creating stabilised amorphous drug-polymer composites. In further improving drug potency and mitigating solubility-limited bioavailability, a candidate based on a phosphate ester prodrug was identified that, although having excellent bioavailability, exhibited unacceptable pharmacokinetics. Based on in silico modelling and a site of absorption study it was confirmed that creating an extended release formulation could provide the desired pharmacokinetic profile. The optimised formulation showed good antiviral activity when dosed employing a once or twice a day regimen.
journal_name
Drug Discov Todayjournal_title
Drug discovery todayauthors
Timmins P,Brown J,Meanwell NA,Hanna GJ,Zhu L,Kadow JFdoi
10.1016/j.drudis.2014.03.025subject
Has Abstractpub_date
2014-09-01 00:00:00pages
1288-93issue
9eissn
1359-6446issn
1878-5832pii
S1359-6446(14)00119-6journal_volume
19pub_type
杂志文章abstract::This review provides an update on the promises and pitfalls when using in vitro bioassays to evaluate beneficial and adverse health effects of botanicals and botanical preparations. Important issues addressed in the paper are: (i) the type of assays and biological effects available; (ii) false-positives, false-negativ...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2017.05.002
更新日期:2017-08-01 00:00:00
abstract::Nonclinical safety testing of new biotherapeutic entities represents its own challenges and opportunities in drug development. Hot topics in this field have been discussed recently at the 2nd Annual BioSafe European General Membership Meeting. In this feature article, discussions on the challenges surrounding the use ...
journal_title:Drug discovery today
pub_type:
doi:10.1016/j.drudis.2013.08.003
更新日期:2013-12-01 00:00:00
abstract::Lipidomics is a rapidly growing technology that can be used in biomedical research to study disease mechanisms, identify novel disease biomarkers and drug efficacy biomarkers, and reveal off-target effects. Lipidomics can also be used to elucidate the mechanism of action of different drug compounds or as readouts in M...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2013.09.008
更新日期:2014-02-01 00:00:00
abstract::Long-acting drug nanosuspension formulations are coming to the fore as controlled release strategies for several medical conditions and as a preventative measure against HIV infection. However, such delivery systems must, by necessity, be given by hypodermic injection, typically into muscle. This poses problems for pa...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2017.10.013
更新日期:2018-05-01 00:00:00
abstract::Posttranslational modifications of proteins such as phosphorylation have been recognized as pivotal modulators of biological activity in healthy and diseased tissues. Sulfation is a key posttranslational modification the role of which in physiology and pathology is only now becoming appreciated. Whereas phosphorylatio...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/S1359-6446(04)03261-1
更新日期:2004-11-15 00:00:00
abstract::SNPs can alter protein function and phenotype, leading to altered pharmacogenomic drug profiles. The exponential number of SNPs makes it impossible to perform wet laboratory experiments to determine the biological significance of each one. However, bioinformatics tools can be used to screen for potentially deleterious...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2011.07.005
更新日期:2011-09-01 00:00:00
abstract::Epigenetic covalent modifications of DNA and chromatin proteins strongly affect gene expression and cellular activity, and epigenetic misregulation occurs in several diseases, especially cancer. First-generation drugs targeting the relatively promiscuous DNA methylation and histone acetylation modifiers have had succe...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2009.10.010
更新日期:2010-01-01 00:00:00
abstract::Healthcare systems are faced with the challenge of providing innovative treatments, while shouldering high drug costs that pharmaceutical companies justify by the high costs of R&D. An emergent technology that could transform R&D efficiency is organ-on-a-chip. The technology bridges the gap between preclinical testing...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2019.06.003
更新日期:2019-09-01 00:00:00
abstract::Micro RNAs (miRNAs) are a class of naturally occurring ∼ 22 nt long non-coding small RNA molecules that regulate the expression of a wide range of genes involved in development, growth, proliferation and apoptosis. miRNAs are evolutionarily conserved from plants to animals, and they regulate and fine-tune a diverse ar...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2010.07.003
更新日期:2010-09-01 00:00:00
abstract::Covalent allosteric modulators possess the pharmacological advantages (high potency, extended duration of action and low drug resistance) of covalent ligands and the additional benefit of the higher specificity and lower toxicity of allosteric modulators. This approach is gaining increasing recognition as a valuable t...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2016.11.013
更新日期:2017-02-01 00:00:00
abstract::Identification and validation of viable targets is an important first step in drug discovery and new methods, and integrated approaches are continuously explored to improve the discovery rate and exploration of new drug targets. An in silico machine learning method, support vector machines, has been explored as a new ...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2007.02.015
更新日期:2007-04-01 00:00:00
abstract::Since being introduced to the field of drug discovery at Zeneca Pharmaceuticals in 1991, it has become apparent to me that a blizzard of revolutionary novel approaches has swept through the pharmaceutical industry. Now, the discovery process has become completely transformed and the race to develop commercially succes...
journal_title:Drug discovery today
pub_type: 杂志文章
doi:10.1016/s1359-6446(98)01289-6
更新日期:1999-01-01 00:00:00
abstract::During the past 10 years, substantial progress has been made in the discovery and development of small molecule glutamate carboxypeptidase II (GCP II) inhibitors. These inhibitors have provided the necessary tools to investigate the physiological role of GCP II as well as the potential therapeutic benefits of its inhi...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2007.07.010
更新日期:2007-09-01 00:00:00
abstract::Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation. In moderate-to-severe COPD, long-acting bronchodilators are the basis of therapy. Inhaled long-acting β(2)-agonists (LABAs) are used for the treatment of COPD. LABAs have been in use since the 1990s enabling persistent bro...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2011.11.002
更新日期:2012-05-01 00:00:00
abstract::The physiological levels of many clinically important proteins are regulated through cellular mechanisms that control the stability and translational efficiency of mRNA. These post-transcriptional processes, which play a critical role in the regulation of gene expression, depend on interactions of specific trans-actin...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2007.05.009
更新日期:2007-07-01 00:00:00
abstract::Polymer-drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such a...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2020.06.028
更新日期:2020-09-01 00:00:00
abstract::Here, we describe a novel workflow combining informatic and experimental approaches to enable evidence-based prioritising of targets from large sets in parallel. High-throughput protein production and biophysical fragment screening is used to identify those targets that are tractable and ligandable. As proof of concep...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2020.09.003
更新日期:2020-09-10 00:00:00
abstract::Protein expression therapy using nucleic acid macromolecules (NAMs) as a new paradigm in medicine has recently gained immense therapeutic potential. With the advancement of nonviral delivery it has been possible to target NAMs against cancer, immunodeficiency and infectious diseases. Owing to the complex and fragile s...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2015.11.012
更新日期:2016-03-01 00:00:00
abstract::In the past five years therapeutic monoclonal antibodies have established themselves as perhaps the most important and rapidly expanding class of therapeutic drugs. More than 25% of pharmacological agents that are currently under development are based on antibodies and the total income generated from them in 2002 exce...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/s1359-6446(03)02714-4
更新日期:2003-06-01 00:00:00
abstract::With the aging of the general population, there is an increasing need for bone defect repair, prompting the development of reliable alternatives to autologous bone grafting, without the usually associated major drawbacks (i.e., limited volume and severe postoperative pain). Given the crucial role that miRNAs appear to...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2017.04.007
更新日期:2017-07-01 00:00:00
abstract::The biopharmaceutical industry has undergone remarkable changes over the past half century, driven largely by a need to offset the ever-rising costs of developing new medicines. In this report, we aggregated information about the creation and fate of all clinical-stage biopharmaceutical companies, assessing trends ove...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2020.10.026
更新日期:2021-01-01 00:00:00
abstract::Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevan...
journal_title:Drug discovery today
pub_type: 杂志文章
doi:10.1016/s1359-6446(00)01533-6
更新日期:2000-08-01 00:00:00
abstract::Retinal photoreceptors continually endure stresses associated with prolonged light exposure and the metabolic demands of dark adaptation. Although healthy photoreceptors are able to withstand these stresses for several decades, the disease-affected retina functions at a reduced capacity and is at an increased risk for...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2019.11.013
更新日期:2020-02-01 00:00:00
abstract::Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevan...
journal_title:Drug discovery today
pub_type: 杂志文章
doi:10.1016/s1359-6446(01)02006-2
更新日期:2001-11-15 00:00:00
abstract::Annotating the druggable genome estimates the potential maximum size of the playing field for current small-molecule drug design but It does not consider biologicals or future breakthroughs in medicinal chemistry or biology. ...
journal_title:Drug discovery today
pub_type: 杂志文章
doi:10.1016/S1359-6446(05)03666-4
更新日期:2005-12-01 00:00:00
abstract::Rab GTPases constitute the largest family of small GTPases. Rabs regulate not only membrane trafficking but also cell signaling, growth and survival, and development. Increasingly, Rabs and their effectors are shown to be overexpressed or subject to loss-of-function mutations in a variety of disease settings, includin...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2017.03.012
更新日期:2017-08-01 00:00:00
abstract::Drug-delivery technologies for modified drug release have been in existence for decades, but their utilization has been largely limited to post-launch efforts improving therapeutic outcomes. Recently, they have gained renewed importance because the pharmaceutical industry is steadily shifting to a more integrated disc...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2020.12.008
更新日期:2020-12-14 00:00:00
abstract::Translating academic medical research into new therapies is an important challenge for the biopharmaceutical industry and investment communities, which have historically favored later-stage assets with lower risk and clearer commercial value. The Stanford SPARK program is an innovative model for addressing this challe...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/j.drudis.2017.03.015
更新日期:2017-07-01 00:00:00
abstract::Biomedical scientists tend to focus on only a small fraction of the proteins encoded by the human genome despite overwhelming genetic evidence that many understudied proteins are important for human disease. One of the best ways to interrogate the function of a protein and to determine its relevance as a drug target i...
journal_title:Drug discovery today
pub_type: 杂志文章
doi:10.1016/j.drudis.2019.06.020
更新日期:2019-11-01 00:00:00
abstract::Drug discovery is a time consuming and costly process. Recently, a trend towards the use of in silico computational chemistry and molecular modeling for computer-aided drug design has gained significant momentum. This review investigates the application of free and/or open-source software in the drug discovery process...
journal_title:Drug discovery today
pub_type: 杂志文章,评审
doi:10.1016/S1359-6446(05)03692-5
更新日期:2006-02-01 00:00:00